Breakdown of immune privilege and spontaneous autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen

Reiko Horai*, Phyllis B. Silver, Jun Chen, Rajeev K. Agarwal, Wai Po Chong, Yingyos Jittayasothorn, Mary J. Mattapallil, Sonia Nguyen, Kannan Natarajan, Rafael Villasmil, Peng Wang, Zaruhi Karabekian, Simon D. Lytton, Chi Chao Chan, Rachel R. Caspi*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

83 Citations (Scopus)

Abstract

Despite presence of circulating retina-specific T cells in healthy individuals, ocular immune privilege usually averts development of autoimmune uveitis. To study the breakdown of immune privilege and development of disease, we generated transgenic (Tg) mice that express a T cell receptor (TCR) specific for interphotoreceptor retinoid-binding protein (IRBP), which serves as an autoimmune target in uveitis induced by immunization. Three lines of TCR Tg mice, with different levels of expression of the transgenic R161 TCR and different proportions of IRBP-specific CD4⁺ T cells in their peripheral repertoire, were successfully established. Importantly, two of the lines rapidly developed spontaneous uveitis, reaching 100% incidence by 2 and 3 months of age, respectively, whereas the third appeared "poised" and only developed appreciable disease upon immune perturbation. Susceptibility roughly paralleled expression of the R161 TCR. In all three lines, peripheral CD4⁺ T cells displayed a naïve phenotype, but proliferated in vitro in response to IRBP and elicited uveitis upon adoptive transfer. In contrast, CD4⁺ T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory cells that appeared to have been peripherally converted from conventional CD4⁺ T cells rather than thymically derived. Thus, R161 mice provide a new and valuable model of spontaneous autoimmune disease that circumvents the limitations of active immunization and adjuvants, and allows to study basic mechanisms involved in maintenance and breakdown of immune homeostasis affecting immunologically privileged sites such as the eye.
Original languageEnglish
Pages (from-to)21-33
Number of pages13
JournalJournal of Autoimmunity
Volume44
DOIs
Publication statusPublished - Aug 2013

Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

User-Defined Keywords

  • Autoimmune uveitis
  • Immune privilege
  • Spontaneous disease
  • TCR transgenic mouse

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